title: Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia.
abstract: Differentiation arrest is a hallmark of acute leukemia. Genomic alterations in B cell differentiation factors such as PAX5, IKZF1, and EBF-1 have been identified in more than half of all cases of childhood B precursor acute lymphoblastic leukemia (ALL). Here, we describe a perturbed epigenetic and transcriptional regulation of ZNF423 in ALL as a novel mechanism interfering with B cell differentiation. Hypomethylation of ZNF423 regulatory sequences and BMP2 signaling result in transactivation of ZNF423α and a novel ZNF423β-isoform encoding a nucleosome remodeling and histone deacetylase complex-interacting domain. Aberrant ZNF423 inhibits the transactivation of EBF-1 target genes and leads to B cell maturation arrest in vivo. Importantly, ZNF423 expression is associated with poor outcome of ETV6-RUNX1-negative B precursor ALL patients. Our work demonstrates that ALL is more than a genetic disease and that epigenetics may uncover novel mechanisms of disease with prognostic implications.
authors.affiliation: Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Harder
authors.forename: Georg
authors.initials: G
authors.lastname: Eschenburg
authors.forename: Antonia
authors.initials: A
authors.lastname: Zech
authors.forename: Neele
authors.initials: N
authors.lastname: Kriebitzsch
authors.forename: Benjamin
authors.initials: B
authors.lastname: Otto
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Anna-Sophie
authors.initials: AS
authors.lastname: Behlich
authors.forename: Kevin
authors.initials: K
authors.lastname: Dierck
authors.forename: Bine
authors.initials: B
authors.lastname: Klingler
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
authors.forename: Martin A
authors.initials: MA
authors.lastname: Horstmann
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D011506:Proteins; D051785:Smad Proteins; D015534:Trans-Activators; C525718:BMP2 protein, human; C081976:EBF1 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C031017:ornithine decarboxylase antizyme